title: The association between ß-glucocerebrosidase mutations and parkinsonism.
abstract: Mutations in the ß-glucocerebrosidase gene (GBA), which encodes the lysosomal enzyme ß-glucocerebrosidase, have traditionally been implicated in Gaucher disease, an autosomal recessive lysosomal storage disorder. Yet the past two decades have yielded an explosion of epidemiological and basic-science evidence linking mutations in GBA with the development of Parkinson disease (PD) as well. Although the specific contribution of mutant GBA to the pathogenesis of parkinsonism remains unknown, evidence suggests that both loss of function and toxic gain of function by abnormal ß-glucocerebrosidase may be important, and implicates a close relationship between ß-glucocerebrosidase and α-synuclein. Furthermore, multiple lines of evidence suggest that although GBA-associated PD closely mimics idiopathic PD (IPD), it may present at a younger age, and is more frequently complicated by cognitive dysfunction. Understanding the clinical association between GBA and PD, and the relationship between ß-glucocerebrosidase and α-synuclein, may enhance understanding of the pathogenesis of IPD, improve prognostication and treatment of GBA carriers with parkinsonism, and furthermore inform therapies for IPD not due to GBA mutations.
authors.affiliation: Department of Neurology, Beth Israel Medical Center, 10 Union Square East, Suite 5K, New York, NY 10003, USA. matswan@chpnet.org
authors.forename: Matthew
authors.initials: M
authors.lastname: Swan
authors.forename: Rachel
authors.initials: R
authors.lastname: Saunders-Pullman
mesh_terms: D058068:Endophenotypes; D005776:Gaucher Disease / Q000235:genetics; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D059906:Neuroimaging; D020734:Parkinsonian Disorders / Q000175:diagnosis / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D051844:alpha-Synuclein / Q000235:genetics
chemical_list: D051844:alpha-Synuclein; D005962:Glucosylceramidase